The Seattle group knew that the anoxic response was not just an exaggerated version of the hypoxic (low oxygen) response, because hypoxia-inducible factor 1 (HIF-1) was not needed for survival in anoxia. They conducted an RNAi screen, and found that two genes are uniquely required for survival in anoxia: san-1 (suspended animation 1, which is similar to the spindle checkpoint gene mad3) and mdf-2 (similar to mad2). Worm embryos lacking either protein die after their cells fail to arrest in metaphase during anoxia.
Anoxic worm cells arrest at several points in the cell cycle, presumably using a variety of proteins to mediate these arrests. And the cell cycle is not an anoxic worm's only concern. “There are some pretty profound things it has to think about to do with bioenergetics,” says Roth. Entropy must be fought, and in particular ion gradients need to be maintained. “If you don't do that,” says Roth, “you're dead.”
The details of how that is achieved remain a mystery, but Roth has ideas about the general goal. For an anoxic worm, he says, “you may not have the furnace, but you better not blow out the pilot light. We think glycolysis is the pilot light.”
Anoxic survival capabilities extend up to larger animals—pigs can have all their blood replaced by salt solutions for up to two hours, then recover and show normal memory retention and learning. These pigs, and humans who suffer massive blood loss, are helped by treatments that lower core body temperatures. Roth hopes that lessons from worms will enable more directed treatments so that humans can perhaps match worms in their feats of reanimatology.